Eligibility, uptake and response to germline genetic testing in women with DCIS.

Background: Ductal carcinoma in situ (DCIS) is a malignant, yet pre-invasive disease of the breast. While the majority of DCIS have low risk of recurrence, a subset of women with germline pathogenic variants (PV) in cancer predisposition genes are at increased risk for recurrence. Uptake of genetic testing and subsequent surgical intervention in women with DCIS has not been well-studied. The aim of this study was to evaluate test eligibility parameters, uptake of clinical testing, impact on surgical decision making and second cancer events (SCE) in women with DCIS. Methods: Four-hundred eighty-four women diagnosed with unilateral DCIS 2001-2020 were eligible for this study. Demographic, commercial genetic test results and surgical procedures were extracted from the database. Test-eligibility was assigned using National Comprehensive Cancer Network (NCCN) criteria. Panel genetic testing was performed in the research laboratory across 94 cancer predisposition genes. Statistical analyses were performed using Fisher's exact tests and Chi-square analyses with p < 0.05 defining significance. Results: Forty-four percent of women were test-eligible at diagnosis of which 63.4% pursued genetic testing before definitive surgery; 9.9% pursued testing only after a second cancer event. Bilateral mastectomy (BM) was significantly higher (p<0.001) in women who had testing before definitive surgery (46.9%) compared to those who had testing afterword (10.8%) and in women who underwent testing before definitive surgery with PV (75%) compared to those without PV (37.5%. p=0.045). Of the 39 women with PV, 20 (51.3%) were detected only in the research setting, with 7 (17.9%) of these women not eligible for genetic testing based on NCCN criteria. In women who did not undergo BM at diagnosis, SCE were significantly higher (p=0.001) in women with PV (33.3%) compared to those without PV (11.9%). Conclusion: Pursuit of genetic testing and subsequent use of risk-reducing surgeries in women with PV was suboptimal in women with a primary diagnosis of DCIS. In conjunction, >50% of PV were detected only in the research setting. Because omission of genetic testing in women with DCIS may represent a lost opportunity for prevention, genetic testing at the time of diagnosis should be standard for all women with DCIS.

Pathologic response of ductal carcinoma in situ to neoadjuvant systemic treatment in HER2-positive breast cancer.

PURPOSE: The presence of extensive ductal carcinoma in situ (DCIS) adjacent to HER2-positive invasive breast cancer (IBC) is often a contra-indication for breast-conserving surgery, even in case of excellent treatment response of the invasive component. Data on the response of DCIS to neoadjuvant systemic treatment (NST) are limited. Therefore, we estimated the response of adjacent DCIS to NST-containing HER2-blockade in HER2-positive breast cancer patients and assessed the association of clinicopathological and radiological factors with response. METHODS: Pre-NST biopsies were examined to determine presence of DCIS in all women with HER2-positive IBC treated with trastuzumab-containing NST ± pertuzumab between 2004 and 2017 in a comprehensive cancer center. When present, multiple DCIS factors, including grade, calcifications, necrosis, hormone receptor, and Ki-67 expression, were scored. Associations of clinicopathological and radiological factors with complete response were assessed using logistic regression models. RESULTS: Adjacent DCIS, observed in 138/316 patients with HER2-positive IBC, was eradicated after NST in 46% of patients. Absence of calcifications suspicious for malignancy on pre-NST mammography (odds ratio (OR) 3.75; 95% confidence interval (95% CI) 1.72-8.17), treatment with dual HER2-blockade (OR 2.36; 95% CI 1.17-4.75), a (near) complete response on MRI (OR 3.55; 95% CI 1.31-9.64), and absence of calcifications (OR 3.19; 95% CI 1.34-7.60) and Ki-67 > 20% in DCIS (OR 2.74; 95% CI 1.09-6.89) on pre-NST biopsy were significantly associated with DCIS response. CONCLUSIONS: As DCIS can respond to NST containing HER2-blockade, the presence of extensive DCIS in HER2-positive breast cancer before NST should not always indicate a mastectomy. The predictive factors we found could be helpful when considering breast-conserving surgery in these patients.

Intratumoral Heterogeneity in Ductal Carcinoma In Situ: Chaos and Consequence.

Ductal carcinoma in situ (DCIS) is a non-invasive proliferative growth in the breast that serves as a non-obligate precursor to invasive ductal carcinoma. The widespread adoption of screening mammography has led to a steep increase in the detection of DCIS, which now comprises approximately 20% of new breast cancer diagnoses in the United States. Interestingly, the intratumoral heterogeneity (ITH) that has been observed in invasive breast cancers may have been established early in tumorigenesis, given the vast and varied ITH that has been detected in DCIS. This review will discuss the intratumoral heterogeneity of DCIS, focusing on the phenotypic and genomic heterogeneity of tumor cells, as well as the compositional heterogeneity of the tumor microenvironment. In addition, we will assess the spatial heterogeneity that is now being appreciated in these lesions, and summarize new approaches to evaluate heterogeneity of tumor and stromal cells in the context of their spatial organization. Importantly, we will discuss how a growing understanding of ITH has led to a more holistic appreciation of the complex biology of DCIS, specifically its evolution and natural history. Finally, we will consider ways in which our knowledge of DCIS ITH might be translated in the future to guide clinical care for DCIS patients.

Clinical risk score to predict likelihood of recurrence after ductal carcinoma in situ treated with breast-conserving surgery.

PURPOSE: A majority of women with ductal carcinoma in situ (DCIS) receive breast-conserving surgery (BCS) but then face a risk of ipsilateral breast tumor recurrence (IBTR) which can be either recurrence of DCIS or invasive breast cancer. We developed a score to provide individualized information about IBTR risk to guide treatment decisions. METHODS: Data from 2762 patients treated with BCS for DCIS at centers within the National Comprehensive Cancer Network (NCCN) were used to identify statistically significant non-treatment-related predictors for 5-year IBTR. Factors most associated with IBTR were estrogen-receptor status of the DCIS, presence of comedo necrosis, and patient age at diagnosis. These three parameters were used to create a point-based risk score. Discrimination of this score was assessed in a separate DCIS population of 301 women (100 with IBTR and 200 without) from Kaiser Permanente Northern California (KPNC). RESULTS: Using NCCN data, the 5-year likelihood of IBTR without adjuvant therapy was 9% (95% CI 5-12%), 23% (95% CI 13-32%), and 51% (95% CI 26-75%) in the low, intermediate, and high-risk groups, respectively. Addition of the risk score to a model including only treatment improved the C-statistic from 0.69 to 0.74 (improvement of 0.05). Cross-validation of the score resulted in a C-statistic of 0.76. The score had a c-statistic of 0.67 using the KPNC data, revealing that it discriminated well. CONCLUSIONS: This simple, no-cost risk score may be used by patients and physicians to facilitate preference-based decision-making about DCIS management informed by a more accurate understanding of risks.

Polyphenolics from mango (Mangifera indica L.) suppress breast cancer ductal carcinoma in situ proliferation through activation of AMPK pathway and suppression of mTOR in athymic nude mice.

The objective of this study was to assess the underlying mechanisms of mango polyphenol decreased cell proliferation and tumor volume in ductal carcinoma in situ breast cancer. We hypothesized that mango polyphenols suppress signaling along the AKT/mTOR axis while up-regulating AMPK. To test this hypothesis, mango polyphenols (0.8 mg gallic acid equivalents per day) and pyrogallol (0.2 mg/day) were administered for 4 weeks to mice xenografted with MCF10DCIS.com cells subcutaneously (n=10 per group). Tumor volumes were significantly decreased, both mango and pyrogallol groups displayed greater than 50% decreased volume compared to control. There was a significant reduction of phosphorylated protein levels of IR, IRS1, IGF-1R, and mTOR by mango; while pyrogallol significantly reduced the phosphorylation levels of IR, IRS1, IGF-1R, p70S6K, and ERK. The protein levels of Sestrin2, which is involved in AMPK-signaling, were significantly elevated in both groups. Also, mango significantly elevated AMPK phosphorylation and pyrogallol significantly elevated LKB1 protein levels. In an in vitro model, mango and pyrogallol increased reactive oxygen species (ROS) generation and arrested cells in S phase. In silico modeling indicates that pyrogallol has the potential to bind directly to the allosteric binding site of AMPK, inducing activation. When AMPK expression was down-regulated using siRNA in vitro, pyrogallol reversed the reduced expression of AMPK. This indicates that pyrogallol not only activates AMPK, but also increases constitutive protein expression. These results suggest that mango polyphenols and their major microbial metabolite, pyrogallol, inhibit proliferation of breast cancer cells through ROS-dependent up-regulation of AMPK and down-regulation of the AKT/mTOR pathway.

Tamoxifen Initiation After Ductal Carcinoma In Situ.

BACKGROUND: Endocrine therapy initiation after ductal carcinoma in situ (DCIS) is highly variable and largely unexplained. National guidelines recommend considering tamoxifen for women with estrogen receptor-positive (ER+) DCIS or who undergo excision alone. We evaluated endocrine therapy use after DCIS over a 15-year period in an integrated health care setting to identify factors related to initiation. METHODS: Female Group Health Cooperative enrollees ages 18-89 years with a DCIS diagnosis during 1996-2011 were eligible for inclusion. Endocrine therapy was identified through pharmacy records. Tumor and treatment information were from tumor registry reports; demographics and other risk factors were from questionnaires and electronic medical records. Relative risks (RRs) and 95% confidence intervals (CIs) for endocrine therapy initiation were calculated using multivariable generalized linear models. RESULTS: We identified 727 women with a DCIS diagnosis, including 163 (22%) who initiated endocrine therapy (149 tamoxifen, 14 aromatase inhibitor). Younger women were more likely to initiate endocrine therapy (RR 1.69; 95% CI 1.16-2.46 for ages 45-54 vs. 65-74 years). Compared with breast-conserving surgery (BCS) with radiation, women who had BCS alone (RR 0.46; 95% CI 0.25-0.84) or mastectomy (RR 0.54; 95% CI 0.39-0.75) were less likely to use endocrine therapy. ER testing increased from 4% of DCIS cases in 2001 to 71% in 2011; however, endocrine therapy initiation decreased from 58% of ER+ DCIS in 2001-2005 to 37% in 2009-2011. CONCLUSION: Increasing ER testing since 2001 has not corresponded to parallel increases in endocrine therapy initiation. Age, surgery, and radiation were the primary factors associated with initiation. IMPLICATIONS FOR PRACTICE: National guidelines recommend considering tamoxifen for women with ductal carcinoma in situ (DCIS) who are estrogen receptor-positive (ER+) or who undergo excision alone. In this study, the rapid increase in ER testing caused by tamoxifen's approval in 2000 did not lead to increases in endocrine therapy initiation, despite recognition of an increasing number of DCIS tumors as ER+ each year. Contrary to the suggested guidelines, women who had breast-conserving surgery without radiation were less likely to use tamoxifen than those who had radiation. Future Food and Drug Administration approval of new endocrine agents for DCIS (such as aromatase inhibitors) may provide an opportunity to reemphasize benefits by ER and surgery status.

Elevated ARG1 expression in primary monocytes-derived macrophages as a predictor of radiation-induced acute skin toxicities in early breast cancer patients.

Radiation therapy (RT) the front-line treatment after surgery for early breast cancer patients is associated with acute skin toxicities in at least 40% of treated patients. Monocyte-derived macrophages are polarized into functionally distinct (M1 or M2) activated phenotypes at injury sites by specific systemic cytokines known to play a key role in the transition between damage and repair in irradiated tissues. The role of M1 and M2 macrophages in RT-induced acute skin toxicities remains to be defined. We investigated the potential value of M1 and M2 macrophages as predictive factors of RT-induced skin toxicities in early breast cancer patients treated with adjuvant RT after lumpectomy. Blood samples collected from patients enrolled in a prospective clinical study (n = 49) were analyzed at baseline and after the first delivered 2Gy RT dose. We designed an ex vivo culture system to differentiate patient blood monocytes into macrophages and treated them with M1 or M2-inducing cytokines before quantitative analysis of their "M1/M2" activation markers, iNOS, Arg1, and TGFß1. Statistical analysis was performed to correlate experimental data to clinical assessment of acute skin toxicity using Common Toxicity Criteria (CTC) grade for objective evaluation of skin reactions. Increased ARG1 mRNA significantly correlated with higher grades of erythema, moist desquamation, and CTC grade. Multivariate analysis revealed that increased ARG1 expression in macrophages after a single RT dose was an independent prognostic factor of erythema (p = 0 .032), moist desquamation (p = 0 .027), and CTC grade (p = 0 .056). Interestingly, multivariate analysis of ARG1 mRNA expression in macrophages stimulated with IL-4 also revealed independent prognostic value for predicting acute RT-induced toxicity factors, erythema (p = 0 .069), moist desquamation (p = 0 .037), and CTC grade (p = 0 .046). To conclude, our findings underline for the first time the biological significance of increased ARG1 mRNA levels as an early independent predictive biomarker of RT-induced acute skin toxicities.

Treatment patterns for ductal carcinoma in situ from 2000-2010 across six integrated health plans.

Considerable debate exists about the optimal treatment of ductal carcinoma in situ (DCIS). Using electronic data sources, we examined first course treatment patterns among women aged 18 years and older diagnosed with DCIS between 2000-2010 from six Kaiser Permanente (KP) regions. We calculated the proportion of patients receiving breast conserving surgery (BCS), BCS plus radiation therapy, unilateral mastectomy, bilateral mastectomy, and hormone therapy. Multinomial logistic regression was used to assess the association between patient characteristics and treatment. We included 9,437 women: 1,086 (11.5%) African-American; 1,455 (15.4%) Asian; 918 (9.7%) Hispanic; and 5,978 (63.3%) non-Hispanic white. Most cases (42.2%) received BCS plus radiation as their initial treatment. Nearly equal numbers of women received BCS without radiation (28.5%) or unilateral mastectomy (24.6%). Use of bilateral mastectomy was uncommon (4.7%), and most women (72.2%) did not receive hormone therapy has part of their first course treatment. We observed statistically significant differences in treatment patterns for DCIS by KP region and patient age. Predictably, nuclear grade and the presence of comorbidities were associated with first course treatment for DCIS. We observed statistically significant increases in BCS plus radiation therapy and bilateral mastectomy over time. Although still uncommon, the frequency of bilateral mastectomy increased from 2.7% in 2000 to 7.0% in 2010. We also observed differences in treatment by race/ethnicity. Our findings help illustrate the complex nature of DCIS treatment in the United States, and highlight the need for evidence based guidelines for DCIS care.

Variation in detection of ductal carcinoma in situ during screening mammography: a survey within the International Cancer Screening Network.

BACKGROUND: There is concern about detection of ductal carcinoma in situ (DCIS) in screening mammography. DCIS accounts for a substantial proportion of screen-detected lesions but its effect on breast cancer mortality is debated. The International Cancer Screening Network conducted a comparative analysis to determine variation in DCIS detection. PATIENTS AND METHODS: Data were collected during 2004-2008 on number of screening examinations, detected breast cancers, DCIS cases and Globocan 2008 breast cancer incidence rates derived from national or regional cancer registers. We calculated screen-detection rates for breast cancers and DCIS. RESULTS: Data were obtained from 15 screening settings in 12 countries; 7,176,050 screening examinations; 29,605 breast cancers and 5324 DCIS cases. The ratio between highest and lowest breast cancer incidence was 2.88 (95% confidence interval (CI) 2.76-3.00); 2.97 (95% CI 2.51-3.51) for detection of breast cancer; and 3.49 (95% CI 2.70-4.51) for detection of DCIS. CONCLUSIONS: Considerable international variation was found in DCIS detection. This variation could not be fully explained by variation in incidence nor in breast cancer detection rates. It suggests the potential for wide discrepancies in management of DCIS resulting in overtreatment of indolent DCIS or undertreatment of potentially curable disease. Comprehensive cancer registration is needed to monitor DCIS detection. Efforts to understand discrepancies and standardise management may improve care.